Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens

Abstract

One therapeutic paradigm for cocaine abuse is a 24-h ‘agonist’ treatment which reduces reinforcing effects in a manner similar to the methadone maintenance model for heroin. However, 24-h dosing of dopamine (DA) agonists may induce side effects of insomnia and psychosis, as well as anergia and anhedonia which may actually potentiate abuse. Thus, it is important to determine the daily dose duration of potential treatments such as direct (e.g. pramipexole) and indirect (e.g. GBR 12909) DA agonists, that may induce cross-tolerance with cocaine. We gave a cocaine challenge (15 mg/kg i.p.) on withdrawal day 7 and recorded ambulations and a behavioral rating. We found that 20- and 24-, but not 16-h, daily dosing with cocaine (40 mg/kg), for 14 days, induced tolerance. Pramipexole (4 mg/kg), administered for 24 but not 12 h per day, for 14 days, induced cocaine cross-tolerance while GBR 12909 (18 mg/kg), administered i.p. over 24 or 16 h a day, for 7 days, did not. Thus daily dosing duration is an important variable in consideration of stimulant abuse treatment.